CN116903522A - Synthesis method of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate - Google Patents
Synthesis method of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate Download PDFInfo
- Publication number
- CN116903522A CN116903522A CN202310863285.0A CN202310863285A CN116903522A CN 116903522 A CN116903522 A CN 116903522A CN 202310863285 A CN202310863285 A CN 202310863285A CN 116903522 A CN116903522 A CN 116903522A
- Authority
- CN
- China
- Prior art keywords
- methyl formate
- trifluoromethyl piperidine
- solvent
- piperidine
- trifluoromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 32
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- JNYLMODTPLSLIF-UHFFFAOYSA-N 6-(trifluoromethyl)pyridine-3-carboxylic acid Chemical group OC(=O)C1=CC=C(C(F)(F)F)N=C1 JNYLMODTPLSLIF-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- 238000001816 cooling Methods 0.000 claims abstract description 4
- 238000001704 evaporation Methods 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- BGQMOFGZRJUORO-UHFFFAOYSA-M tetrapropylammonium bromide Chemical group [Br-].CCC[N+](CCC)(CCC)CCC BGQMOFGZRJUORO-UHFFFAOYSA-M 0.000 claims description 3
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims description 2
- HTMRVANFKHNKPH-UHFFFAOYSA-N 1-o-benzyl 3-o-methyl 6-(trifluoromethyl)piperidine-1,3-dicarboxylate Chemical compound C1C(C(=O)OC)CCC(C(F)(F)F)N1C(=O)OCC1=CC=CC=C1 HTMRVANFKHNKPH-UHFFFAOYSA-N 0.000 claims 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 5
- 238000010586 diagram Methods 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- -1 methyl 1-benzyloxycarbonyl-6-trifluoromethylpiperidine-3-carboxylate compound Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000004075 alteration Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- CGESTEQGJQFKPL-UHFFFAOYSA-N methyl 6-(trifluoromethyl)piperidine-3-carboxylate Chemical compound COC(=O)C1CCC(C(F)(F)F)NC1 CGESTEQGJQFKPL-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- IVCPVUGUFSYYKG-UHFFFAOYSA-M tetra(propan-2-yl)azanium;bromide Chemical compound [Br-].CC(C)[N+](C(C)C)(C(C)C)C(C)C IVCPVUGUFSYYKG-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a synthesis method of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate, and relates to the technical field of organic synthesis. The method comprises the following steps: s1: sequentially adding 6-trifluoromethyl piperidine-3-methyl formate, a solvent, a catalyst and potassium carbonate into a reaction bottle, cooling to 0-5 ℃, dropwise adding benzyl chloroformate for condensation reaction, and continuing to react for 12-14h after the dropwise adding is finished; s2: after the reaction, heating, evaporating the solvent, adding 500mL of water, stirring uniformly, extracting 3 times (3X 600 mL) with methyl tertiary butyl ether, concentrating the extract, and obtaining the product of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate. The invention is different from the prior art in that 6-trifluoromethyl piperidine-3-methyl formate and benzyl chloroformate are used as raw materials, the separation and purification process is simple, the reaction time is short, the product yield is high, the product yield reaches more than 95%, the product purity is high, the energy consumption is low, the environmental pollution is small, and the cost is low, thus being an ideal process for realizing industrial preparation.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate.
Background
1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate is an important fine chemical, and a plurality of fine chemicals can be prepared due to the fact that the molecules contain a plurality of active functional groups. In organic synthesis, as an active intermediate, many types of organic compounds, most of which have high pharmacological activity, can be further synthesized, and some of them have been developed into clinical medicines.
Disclosure of Invention
The invention aims to provide a synthesis method of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate, which aims to solve the problems in the prior art.
In order to achieve the above purpose, the present invention provides the following technical solutions: the synthesis method of the 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate comprises the following steps:
s1: sequentially adding 6-trifluoromethyl piperidine-3-methyl formate, a solvent, a catalyst and potassium carbonate into a reaction bottle, cooling to 0-5 ℃, dropwise adding benzyl chloroformate for condensation reaction, and continuing to react for 12-14h after the dropwise adding is finished;
s2: after the reaction, heating, evaporating the solvent, adding 500mL of water, stirring uniformly, extracting 3 times (3X 600 mL) with methyl tertiary butyl ether, concentrating the extract, and obtaining the product of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate.
Further, in the step S1, the dosage ratio of the methyl 6-trifluoromethyl piperidine-3-carboxylate, benzyl chloroformate, potassium carbonate, catalyst and solvent is 1:0.85-1.17:0.72-0.98:0.01-0.05:1.18-2.13 by mass.
Still further, in the step S1, the catalyst is tetrapropylammonium bromide or tetraisopropylammonium bromide or tetrabutylammonium bromide, preferably tetrabutylammonium bromide.
Still further, in the step S1, the solvent is tetrahydrofuran or dioxane or toluene, preferably tetrahydrofuran.
Further, in the step S1, the amount of the aqueous potassium carbonate solution is such that the ratio of the amount of the aqueous potassium carbonate solution to the amount of the aqueous potassium carbonate solution is 1:1.1 to 1.5 by mass.
Compared with the prior art, the invention has the beneficial effects that:
the synthesis method of the 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate is different from the prior art in that the methyl 6-trifluoromethyl piperidine-3-methyl formate and benzyl chloroformate are used as raw materials to synthesize the methyl 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate, the separation and purification process is simple, the reaction time is short, the product yield is high, the product yield reaches more than 95 percent, the product purity is high, the energy consumption is low, the environmental pollution is small, the cost is low, and the method is an ideal process for realizing industrial preparation.
Drawings
FIG. 1 is a diagram showing the structure of a methyl 1-benzyloxycarbonyl-6-trifluoromethylpiperidine-3-carboxylate compound of the present invention;
FIG. 2 is a diagram showing the structure of the methyl 6-trifluoromethylpiperidine-3-carboxylate compound of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
As shown in fig. 1-2, the present invention provides a technical solution: a method for synthesizing 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate.
The method comprises the following steps:
taking 6-trifluoromethyl piperidine-3-methyl formate, benzyl chloroformate and potassium carbonate as raw materials, cooling to 0-5 ℃ in the presence of a catalyst and a solvent, dropwise adding benzyl chloroformate for condensation reaction, continuing to react for 12 hours after the dropwise adding is finished, heating up after the reaction is finished, evaporating the solvent, adding 500mL of water, uniformly stirring, extracting 3 times (3X 600 mL) with methyl tert-butyl ether, and concentrating the extract to obtain the product 1-benzyloxycarbonyl-6-trifluoromethyl piperidine-3-methyl formate. The dosage proportion of the 6-trifluoromethyl piperidine-3-methyl formate, benzyl chloroformate, potassium carbonate, catalyst and solvent is as follows by mass: methyl 6-trifluoromethylpiperidine-3-carboxylate, benzyl chloroformate, potassium carbonate, catalyst, solvent=1:0.85-1.17:0.72-0.98:0.01-0.05:1.18-2.13. The catalyst is tetrapropylammonium bromide or tetraisopropyl ammonium bromide or tetrabutylammonium bromide, preferably tetrabutylammonium bromide; the solvent is tetrahydrofuran or dioxane or toluene, preferably tetrahydrofuran; the dosage proportion of the potassium carbonate aqueous solution is potassium carbonate with the mass ratio of water=1:1.1-1.5; the temperature of the reaction is 0-5 ℃; the reaction time is 12-14h.
Example 1:
49.8g of solvent, 42.2g of 6-trifluoromethyl piperidine-3-methyl formate and 30.4g of potassium carbonate are added into a 500mL four-port reaction bottle with a thermometer, a stirrer is started to be cooled to 0-5 ℃, 35.6g of benzyl chloroformate is started to be dropwise added, the reaction is continued for 12-14h after the dropwise addition is finished, the temperature is raised after the reaction is finished, 500mL of water is added, the solvent is distilled off, the mixture is stirred uniformly and then extracted for 3 times by methyl tert-butyl ether (3X 600 mL), and the extract is concentrated to obtain the product 1-benzyloxycarbonyl-6-trifluoromethyl piperidine-3-methyl formate, wherein the product yield is 95.07%.
Example 2:
89.9g of solvent, 42.2g of methyl 6-trifluoromethyl piperidine-3-carboxylate and 41.4g of potassium carbonate are added into a 500mL four-port reaction bottle with a thermometer, a stirrer is started to be cooled to 0-5 ℃, 35.6g of benzyl chloroformate is started to be dropwise added, the reaction is continued for 12-14h after the dropwise addition is finished, the temperature is raised after the reaction is finished, 500mL of water is added, the solvent is distilled off, the mixture is stirred uniformly and then extracted for 3 times by methyl tert-butyl ether (3X 600 mL), and the extract is concentrated to obtain the product 1-benzyloxycarbonyl-6-trifluoromethyl piperidine-3-methyl formate, wherein the product yield is 95.61%.
Example 3:
49.8g of solvent, 42.2g of methyl 6-trifluoromethyl piperidine-3-carboxylate and 30.4g of potassium carbonate are added into a 500mL four-port reaction bottle with a thermometer, a stirrer is started to be cooled to 0-5 ℃, 49.4g of benzyl chloroformate is started to be dropwise added, the reaction is continued for 12-14h after the dropwise addition is finished, the temperature is raised after the reaction is finished, 500mL of water is added, the solvent is distilled off, the mixture is stirred uniformly and then extracted for 3 times by methyl tert-butyl ether (3X 600 mL), and the extract is concentrated to obtain the product 1-benzyloxycarbonyl-6-trifluoromethyl piperidine-3-methyl formate, wherein the product yield is 96.24%.
Example 4:
49.8g of solvent, 42.2g of methyl 6-trifluoromethyl piperidine-3-carboxylate and 30.4g of potassium carbonate are added into a 500mL four-port reaction bottle with a thermometer, a stirrer is started to be cooled to 0-5 ℃, 49.4g of benzyl chloroformate is started to be dropwise added, the reaction is continued for 12-14h after the dropwise addition is finished, the temperature is raised after the reaction is finished, 500mL of water is added, the solvent is distilled off, the mixture is stirred uniformly and then extracted for 3 times by methyl tert-butyl ether (3X 600 mL), and the extract is concentrated to obtain the product 1-benzyloxycarbonyl-6-trifluoromethyl piperidine-3-methyl formate, wherein the product yield is 95.73%.
Example 5:
in a 500mL four-port reaction flask equipped with a thermometer, 63.3g of solvent, 42.2g of 6-trifluoromethyl piperidine-3-methyl formate, 33.8g of potassium carbonate and 1.7g of catalyst are added, a stirrer is started, the temperature is reduced to 0-5 ℃, 42.2g of benzyl chloroformate is started to be dropwise added, the reaction is continued for 12-14h after the dropwise addition is finished, the temperature is raised after the reaction is finished, 500mL of water is added, the solvent is distilled off, the mixture is stirred uniformly and then extracted for 3 times (3X 600 mL) by methyl tert-butyl ether, and the extract is concentrated to obtain the product 1-benzyloxycarbonyl-6-trifluoromethyl piperidine-3-methyl formate, wherein the product yield is 95.07%.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made hereto without departing from the spirit and scope of the invention as defined by the appended embodiments and equivalents thereof.
Claims (5)
1. The synthesis method of the 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate is characterized by comprising the following steps of:
s1: sequentially adding 6-trifluoromethyl piperidine-3-methyl formate, a solvent, a catalyst and potassium carbonate into a reaction bottle, cooling to 0-5 ℃, dropwise adding benzyl chloroformate for condensation reaction, and continuing to react for 12-14h after the dropwise adding is finished;
s2: after the reaction, heating, evaporating the solvent, adding 500mL of water, stirring uniformly, extracting 3 times (3X 600 mL) with methyl tertiary butyl ether, concentrating the extract, and obtaining the product of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate.
2. The method for synthesizing 1-benzyloxycarbonyl-6-trifluoromethyl piperidine-3-carboxylic acid methyl ester according to claim 1, wherein the method comprises the following steps: in the step S1, the dosage ratio of the 6-trifluoromethyl piperidine-3-methyl formate, the benzyl chloroformate, the potassium carbonate, the catalyst and the solvent is 1:0.85-1.17:0.72-0.98:0.01-0.05:1.18-2.13 by mass.
3. The method for synthesizing 1-benzyloxycarbonyl-6-trifluoromethyl piperidine-3-carboxylic acid methyl ester according to claim 1, wherein the method comprises the following steps: in the step S1, the catalyst is tetrapropylammonium bromide or tetraisopropyl ammonium bromide or tetrabutylammonium bromide, preferably tetrabutylammonium bromide.
4. The method for synthesizing 1-benzyloxycarbonyl-6-trifluoromethyl piperidine-3-carboxylic acid methyl ester according to claim 1, wherein the method comprises the following steps: in the step S1, the solvent is tetrahydrofuran or dioxane or toluene, preferably tetrahydrofuran.
5. The method for synthesizing 1-benzyloxycarbonyl-6-trifluoromethyl piperidine-3-carboxylic acid methyl ester according to claim 1, wherein the method comprises the following steps: in the step S1, the amount ratio of the aqueous potassium carbonate solution is potassium carbonate to water=1:1.1-1.5 by mass.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310863285.0A CN116903522A (en) | 2023-07-14 | 2023-07-14 | Synthesis method of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310863285.0A CN116903522A (en) | 2023-07-14 | 2023-07-14 | Synthesis method of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116903522A true CN116903522A (en) | 2023-10-20 |
Family
ID=88354313
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310863285.0A Pending CN116903522A (en) | 2023-07-14 | 2023-07-14 | Synthesis method of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116903522A (en) |
-
2023
- 2023-07-14 CN CN202310863285.0A patent/CN116903522A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106810426B (en) | Method for synthesizing cannabidiol | |
| KR101125853B1 (en) | Process for preparing of n-methyl pyrrolidone | |
| CN101058592A (en) | Method of preparing alkyl glycoside from sweet potato starch | |
| CN111100084A (en) | Preparation method of parecoxib sodium | |
| KR20110127082A (en) | Preparation method of alkyllactate and process for preparing lactamide using the same | |
| CN116903522A (en) | Synthesis method of 1-carbobenzoxy-6-trifluoromethyl piperidine-3-methyl formate | |
| CN111285782B (en) | Preparation method of 1-cyano-cyclohexyl acetonitrile | |
| CN114950545B (en) | Oxazolium catalyst for acetaldehyde acyloin condensation reaction, and preparation method and application thereof | |
| CN105732363A (en) | Method for preparing gluconic acid by taking glucose as raw material under different working conditions | |
| CN107021969B (en) | The method that catalysis oxidation prepares biotin precursor ketone acid | |
| JP3986817B2 (en) | A method for producing esters of dicarboxylic acids having 4 to 6 carbon atoms from alkaline waste liquid generated in the caprolactam production process | |
| CN113024411B (en) | Preparation method of tralkoxydim | |
| CN111499497A (en) | Preparation method of thymol | |
| CN115160132B (en) | Production process of benzyl benzoate | |
| CN112778152B (en) | Synthesis method of bilastine intermediate | |
| CN114716341B (en) | Method for preparing dimethenamid by one-pot method | |
| CN103145562A (en) | N-ethyl aniline preparation method | |
| CN111087340B (en) | Preparation method of vilazodone intermediate | |
| CN113735712B (en) | Preparation method of o-nitrobenzaldehyde | |
| CN112625015B (en) | Preparation method of 2- (1, 3-dihydro-2-isobenzofuran) -1-acetophenone compound | |
| CN114195638B (en) | Preparation method of phenyl o-hydroxybenzoate | |
| CN113735755B (en) | Preparation method of amisulpride | |
| CN109232224B (en) | Preparation method of 2-phenylpropionic acid | |
| CN116143622A (en) | Synthesis method of cyclohexanedione intermediate methyl 5-oxohexanoate | |
| CN110862329B (en) | Synthesis method of 7-aminoheptanoic acid hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |